Competition between two HUSH complexes orchestrates the immune response to retroelement invasion.

The human silencing hub (HUSH) preserves genome integrity through the epigenetic repression of invasive genetic elements. However, despite our understanding of HUSH as an obligate complex of three subunits, only loss of MPP8 or Periphilin, but not TASOR, triggers interferon signaling following derepression of endogenous retroelements. Here, we resolve this paradox by characterizing a second HUSH complex that shares MPP8 and Periphilin but assembles around TASOR2, an uncharacterized paralog of TASOR. Whereas HUSH represses LINE-1 retroelements marked by the repressive histone modification H3K9me3, HUSH2 is recruited by the transcription factor IRF2 to repress interferon-stimulated genes. Mechanistically, HUSH-mediated retroelement silencing sequesters the limited pool of the shared subunits MPP8 and Periphilin, preventing TASOR2 from forming HUSH2 complexes and hence relieving the HUSH2-mediated repression of interferon-stimulated genes. Thus, competition between two HUSH complexes intertwines retroelement silencing with the induction of an immune response, coupling epigenetic and immune aspects of genome defense.

Antibiomania: clarithromycin-induced neurotoxicity mimicking autoimmune limbic encephalitis.

We describe a 64-year-old woman with relapsing encephalopathy. She initially presented with 5 days of psychomotor agitation, progressing to mania, psychosis and seizures that mimicked autoimmune limbic encephalitis. During her first hospital admission, extensive investigation failed to establish the underlying cause, and she improved with antiseizure medication alone. After a month at home, she relapsed with identical symptoms, and only then did we recognise that both episodes had been provoked by clarithromycin, prescribed for Helicobacter pylori eradication. Clarithromycin-induced neurotoxicity is rarely reported but likely to be under-recognised. It usually manifests within days of starting treatment, with delirium, mania, psychosis or visual hallucinations, sometimes termed 'antibiomania'. Seizures and status epilepticus appear to be less frequent. A full recovery is expected on stopping the medication.

Lewis Acid-Activated Reactions of Silyl Ketenes for the Preparation of α-Silyl Carbonyl Compounds.

Silyl-substituted ketenes are attractive molecular building blocks due to their stability and ease of storage, as opposed to unstable alkyl and aryl ketenes. To better understand the reactivity of silyl ketenes and, in turn, their use in the preparation of highly functionalized small molecules, the reaction of silyl ketenes with different nucleophiles was studied. The addition of alcohol, amine, or thiol nucleophiles to the central carbon of silyl ketene, followed by proton transfer afforded α-silyl ester, amide, or thio-ester, respectively. Catalytic amounts of Lewis acid greatly increase the rate of the reaction, and the impact of nucleophile, Lewis acid, and silyl substituent are evaluated. The small molecules produced from these reactions give insight into the use of silyl ketenes as building blocks for complex molecular structures.

Therapeutic plasma exchange in neurological disorders: Experience from a tertiary neuroscience centre.

Therapeutic plasma exchange (TPE) involves the extracorporeal separation of plasma from the cellular components of blood with replacement fluid, such as human albumin or fresh frozen plasma. A number of studies across the world revealed that more than one third of TPE procedures were performed for neurological disorders. Myasthenia gravis (MG), Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) were the most frequently cited indications for TPE, followed by multiple sclerosis (MS). However, treatments of these conditions have evolved over the years and it is likely that this has impacted on clinical practice. Here we present our experience of using TPE to treat neurological disorders. We reviewed the medical records of all 63 patients who received 349 procedures over 70 therapeutic cycles between 2012 and 2015 in a tertiary neurology centre. In total only 2 patients with GBS and MG were treated with TPE. The commonest indication was voltage gated potassium channel (VGKC) complex antibody associated disorders followed by CIDP and MS. There were 11 patients with limbic encephalitis. Nine of them had antibodies against VGKC complex and two had N-methyl-D-aspartate (NMDA) receptor antibodies. Sixty four percent of patients with limbic encephalitis and overall 78% of patients responded to TPE. The complication rate associated with this procedure was 8.6 per 100 therapeutic cycle. There was no treatment related mortality. We observed a change in indications of TPE compared to historical studies. It was less frequently used to treated GBS and MG. It was found to be safe and effective.

Organofunctional Silane Modification of Aluminum-Doped Zinc Oxide Surfaces as a Route to Stabilization.

Aluminum-doped zinc oxide (AZO) is a low-temperature processed transparent conductive oxide (TCO) made of earth abundant elements; its applications are currently limited by instability to heat, moisture, and acidic conditions. We demonstrate that the application of an organofunctional silane modifier mitigates AZO degradation and explore the interplay between performance and material composition and morphology. Specifically, we evaluate degradation of bare AZO and APTES (3-aminopropyltriethoxysilane)-modified AZO in response to damp heat (DH, 85 °C, 85% relative humidity) exposure over 1000 h and then demonstrate how surface modification impacts changes in electrical and optical properties and chemical composition in one of the most thorough studies to date. Hall measurements show that the resistivity of AZO increases due to a decrease in electron mobility, with no commensurate change in carrier concentration. APTES decelerates this electrical degradation, without affecting AZO optical properties. Percent transmission and yellowness index of an ensemble of bare and modified AZO are stable upon DH exposure, but haze increases slightly for a discrete sample of modified AZO. Atomic force microscopy (AFM) and optical profilometer (OP) measurements do not show evidence of pitting or delamination after 1000 h DH exposure but indicate a slight increase in surface roughness on both the nanometer and micrometer length scales. X-ray photoelectron spectroscopy data (XPS) reveal that the surface composition of bare and silanized AZO is stable over this time frame; oxygen vacancies, as measured by XPS, are also stable with DH exposure, which, together with transmission and Hall measurements, indicate stable carrier concentrations. However, after 1500 h of DH exposure, only bare AZO shows signs of catastrophic destruction. Comparison of the data presented herein to previous reports indicates that the initial AZO composition and microstructure dictate the degradation profile. This work demonstrates that surface modification slows the bulk degradation of AZO and provides insight into how the material can be more widely used as a transparent electrode in the next generation of optoelectronic devices.

A Literature Review of Eosinophilic Fasciitis with an Illustrative Case.

Eosinophilic fasciitis (EF), a rare connective tissue disorder, was first reported by Lawrence Shulman in 1974. Since then over 300 cases have been reported worldwide. EF has variable clinical presentations and currently does not have internationally accepted diagnostic criteria. Dermatological features are the most ubiquitously present symptoms. It often presents with sclerodermalike skin changes. Extracutaneous presentations, such as arthritis and carpal tunnel syndrome can precede cutaneous changes. The most useful clinical features are the lack of Raynaud's phenomenon, telangiectasia and visceral involvement, differentiating it from Scleroderma. Haematological disorders, solid tumours and autoimmune disorders are frequently associated with EF. Historically, the presence of peripheral eosinophilia, elevated ESR and hypergammaglobulinemia were considered to be diagnostic of EF. It is now well recognised that neither the presence of eosinophilia in the blood nor eosinophilic infiltartion in the fascia is necessary for its diagnosis. An en bloc surgical biopsy including skin, subcutis, fascia and muscle is the gold-standard test for diagnosing EF. Magnetic resonance imaging helps to locate a suitable biopsy site and to monitor treatment response. Although its underlying aetiology is unknown, there is a growing body of evidence supporting an immunological origin. Immunosuppressive drugs are used to treat EF and the corticosteroid is the first line treatment. A significant proportion of patients can develop permanent disabilities such as joint contractures, tendon retraction and subdermal sclerosis. Occasionally it can be treatment refractory or have a relapse-remitting course. We report another case of EF with a literature review.

Polythioether Particles Armored with Modifiable Graphene Oxide Nanosheets.

Facile and scalable fabrication methods are attractive to prepare materials for diverse applications. Herein, a method is presented to prepare cross-linked polymeric nanoparticles with graphene oxide (GO) nanosheets covalently attached to the surface. Alkene-modified GO serves as a surfactant in a miniemulsion polymerization, and the alkene functionalities of GO exposed to the oil-phase are incorporated into the polymer particle through thiol-ene reactions, leaving the unreacted alkene functional groups of the other face of GO available for further functionalization. The surface of GO-armored polymer particles is then modified with a small molecule fluorophore or carboxylic acid functional groups that bind to Fe2 O3 and TiO2 nanoparticles. This methodology provides a facile route to preparing complex hybrid composite materials.

Synthesis of quaternary heterocyclic salts.

The microwave synthesis of twenty quaternary ammonium salts is described. The syntheses feature comparable yields to conventional synthetic methods reported in the current literature with reduced reaction times and the absence of solvent or minimal solvent.